Sedative-Hypnotic Drugs Lecture Notes PDF

Central nervous system depressants Sedative –hypnotic drugs A sedative is defined as a compound that calm anxious and restless individuals. hypnotics cause drowsiness and facilitate sleep which is close to the normal pattern. HISTORY AND CLASSIFICATION From the beginning of the twentieth century, b...

Central nervous system depressants Sedative –hypnotic drugs A sedative is defined as a compound that calm anxious and restless individuals. hypnotics cause drowsiness and facilitate sleep which is close to the normal pattern. HISTORY AND CLASSIFICATION From the beginning of the twentieth century, bromides enjoyed a significant role in the U.S. as sedatives. With the advent of barbiturates in the 1940s, the use of bromides waned. Since then, barbiturates have been used traditionally for the alleviation of pain, anxiety, hypertension, epilepsy, and psychiatric disorders. Eventually, use of barbiturates would be replaced by other sedative-hypnotics (S/H) of comparable strength, namely chloral hydrate and meprobamate. Benzodiazepines would replace the traditional S/H as more effective, less toxic, and less addictive anxiolytics (sedatives). Today, the most popular therapeutic agents for anxiety (used for sedation), hypnosis (used for sleep), or anesthesia (for deep sleep) include buspirone (Buspar) and zolpidem (Ambie®). Benzodiazepines are still frequently employed. With the strict enforcement of federal and state-controlled substances regulations, barbiturates have lost significant influence in both the therapeutic and illicit drug markets. Nevertheless, they are still the cause of 50,000 accidental and intentional poisonings per year, and their synergistic effects with ethanol are one of the leading causes of hospital admissions. BARBITURATES MEDICINAL CHEMISTRY Barbiturates are malonylurea derivatives (diureides), synthesized from malonic acid and urea. Figure 1 The electron negative carbonyl carbons confer an acidic nature to the molecule, thus classifying them as weak acids. Allyl, alkyl, and allocyclic side chains determine their pharmacological classification. Structure of prototype barbiturates. PHARMACOLOGY AND CLINICAL USE Pharmacologically and clinically, barbiturates are classified according to their duration of effect. The presence of longer and bulkier aliphatic and allocyclic side chains (Table 1) produces compounds that range from ultrashort-, short-, and intermediate to long-acting. Their major action is the production of sedation, hypnosis, or anesthesia through central nervous system (CNS) depression. The effect, however, depends largely on the dose, mental status of the patient or individual at the time of ingestion, duration of action of the drug, the physical environment while under the influence, and tolerance of the individual to this class of drugs. These factors determine the probability of a therapeutic or euphoric response. For instance, a 100- mg dose of secobarbital ingested in the home at bedtime to induce sleep would, most likely, only cause a mild euphoria in a habitual user at a social gathering, without significant sedation. TOXICOKINETICS AND METABOLISM An increase in the number of carbons and bulkier side chains results in enhanced lipid solubility, with a corresponding increase in toxicity. Attachment of a methylbutyl (1-mb) and replacement of the C2 with a sulfur group (as with thiopental) decreases its electron negativity, making it less acidic, more lipid soluble. Consequently, thiopental is an ultrashort-acting barbiturate used exclusively as a preoperative sedative/hypnotic. As a class, the barbiturates are largely nonionic, lipid-soluble compounds, and their pKa ranges between 7.2 and 7.9. The dissociation constants, therefore, do not account for differences in duration of action, especially with the long-acting compounds. Rapid movement into and out of the CNS appears to determine rapid onset and short duration. Conversely, the barbiturates with the slowest onset and longest duration of action contain the most polar side chains (ethyl and phenyl with phenobarbital structure, Table 1). Thus, the structure in Table 1 dictates that phenobarbital enters and leaves the CNS very slowly as compared to the more lipophilic thiopental (with intermediate pKa). In addition, the lipid barriers to drug metabolizing enzymes lead to a slower metabolism for the more polar barbiturates, considering that phenobarbital is metabolized to the extent of 10% per day. Similarly, distribution in biological compartments, especially the CNS, is governed by lipid solubility. Metabolism of oxybarbiturates occurs primarily in liver, whereas thiobarbiturates are also metabolized, to a limited extent, in kidney and brain. Phase I reactions introduce polar groups at the C5 position of oxybarbiturates, transforming the radicals to alcohols, ketones, and carboxylic acids. These inactive metabolites are eliminated in urine as glucuronide conjugates. Thiobarbiturates undergo desulfuration, to corresponding oxybarbiturates, and opening of the barbituric acid ring. Side chain oxidation at the C5 position is the most important biotransformation reaction leading to drug detoxification. Table 1 Properties of Barbiturates Sedative/Hypnotic Toxic Concentration Compoundsa R1 Classification Dose (Total mg Daily) (mg/dl) t1/2 (h) pKa Barbital ethyl LA 100–200/300–500 6–8 — 7.8 Phenobarbital phenyl LA 30–90/100–200 4–6 24–140 7.2 Amobarbital isopentyl IA 30–150/100–200 1–3 8–42 7.8 Pentobarbital 1-mb SA 20–150/100 0.5–1.0 16–48 7.9 Secobarbitalb 1-mb SA 30–200/100 0.5–1.0 20–34 7.9 Thiopental 1-mb, C2=S UA 3–5 mg/kg